Herpes Simplex Virus (HSV) is an important human pathogen and a double strand DNA virus. This virus is classified according to different host species, replication cycle time, and its capacity to decompose the cell it infects. The current HSV has two different subtypes one of which infects the mucosal regions of the mouth, pharynx, lips and eyes (HSV-1) and the other of which causes genital system diseases which are sexually transmitted [1]. The incidence of infection, which is generally seen in children, varies according to geographical and socioeconomic conditions. The virus is transmitted by close contact and 90% of the children living in regions of low socioeconomic level are tested seropositive for HSV-1 [2]. In addition, according to American National Eye Institute (NEI), ocular herpes infection has been encountered in 400,000 reported cases in the United States and 50,000 new or repeating cases are encountered each year [3].
HSV infection, after causing vesicular lesions in mucosal epithelial cells, is transmitted to the sensory neurons and followed by a latent infection which may prolong throughout the life of the host [4]. Reactivation of the virus from latency causes recurrent diseases at or near the primary site of infection. The herpes caused by HSV-1 infection are generally not life threatening. However, cornea infection (keratitis), central nervous system infection (encephalitis), and infections in newborns and people having weak immune systems may cause serious diseases [5].
In today's technology, the variety of drugs used for HSV infections is limited. The most important of these drugs used in clinical practice are Acyclovir, Vidarabine, Cidofovir, Trifluridine, Brivudine and Foscarnet [6]. HSV types which are particularly resistant against Acyclovir. Vidarabine and Foscarnet drugs have developed due to the unconscious and continuous use of these anti-herpetic drugs [7-8-9-10]. However, the HSV types which have developed resistance against these drugs due to immune system deficiency particularly in individuals who have received chemotherapy treatment or organ transplant create serious problems in clinical applications. Because of these difficulties that are experienced and the fact that the drug variety in these therapeutic applications is limited, development of new prophylactic and anti-herpetic agents or making the existing systems more efficient has become an important area.
Chlorhexidine (1,1′-hexamethylene-bis[5-(p-chloro-phenyl)-biguanide; C22H30C12N102C6H12O7), which is a reliable and effective chemical in optimized concentrations, is used in gargles, gels and toothpastes in order to prevent dental plaque formation. With the studies conducted, it is observed that chlorhexidine has antimicrobial activity against many microorganism types (yeast, fungus, facultative anaerobe and aerobe bacteria) [11]. In addition to the antimicrobial properties of chlorhexidine, its antiviral activity against Herpes simplex virus is also shown by in vitro and in vivo studies [12]. In in vitro studies, it is determined that chlorhexidine inhibits viral replication of HSV-1 virus in vero cells. Additionally, it is proved in animal studies that chlorhexidine inhibits the virus from proliferating and forming lesions when topically applied on infected skin [13]. Again in the same study, it is determined that chlorhexidine alone has antiviral activity and that its combination with Acyclovir exhibits a synergistic effect. As a conclusion it is shown that the combination group significantly reduced viral replication more than the group to which Acyclovir was administered alone.
It has been known for over a century that boron is an important trace element for plants. It is stated in the studies conducted that this element plays important roles in proton and ion transfer, steroid hormone synthesis and release and in bone and calcium metabolism in animals and humans [14]. In the state of the art applications, antimicrobial activity of various boron compounds on bacterial [15-16] and fungal [17-18] species are demonstrated. It is reported that the formulation made with boric acid heals herpes when applied topically on humans [19].
The U.S. Pat. No. 4,285,934, an application in the state of the art, discloses that combination of boric acid (15%), tannic acid (15%) and salicylic acid (3%) is effective against herpes lesions.
The patent documents no. EP1790349 and WO2005-MX7920050902, other applications in the state of the art, disclose that sodium pentaborate pentahydrate can be used for treatment of viral and bacterial diseases by activating immune system. However it was not mentioned about any antiviral activity of these components on Herpes Simplex Virus and other viruses.
Another component which is pluronics, also known as poloxamer, are the synthetic polymers which have a triblock structure composed of hydrophobic polypropylene oxide and hydrophilic polyethylene oxide units [20]. These polymers are surfactant due to their amphiphilic structures and can interact with the cell membrane. Pluronics can be used in transportation of drugs as the amounts of micelle they form are more than the critical micelle concentration in the solutions [21]. Additionally, they can be used in bioreactors for enhancing cell viability and decreasing agitation stress [22]. Different components of poloxamers are used in nanogel formulation. Thanks to mucoadhesive properties of these polymers, the drug can effectively penetrate into the cell and its efficacy can be enhanced by preventing decomposition thereof.
The United States patent document no. US2007/0141091, one of the applications known in the state of the art, discloses that poloxamer is added at a concentration of 1% (w/v) and it is used topically against infections.